A number of approaches have been utilized in treating malignant growth of tissue cells in humans such as cancers. While the various approaches identified have frequently been successful in treating a particular cancer, one difficulty has been that there are numerous different cancers. Thus, drugs that treat one type of cancer, often are ineffective against a different type of cancer.
One method that attempts to overcome the difficulties resulting from the differences in cancers is immunotherapy. By such an approach, the immune system can select and create the method of treating a specific cancer. Being able to select and/or identify antigens including specific epitopes that can be used in such an approach is extremely important.
Specific peptides that bind human MHC molecules have now been identified for melanoma associated antigens. Darrow, T. L., et al. J Immunol 142: 3329-3335, (1989); Hom, S. S., et al. J Immunother 10: 153-164, (1991); Cox, A. L., et al. Science 264: 716-719 (1994); Olive, D., et al. Cancer Vaccine Symposium. Cancer Research Institute. Oct. 3-4 (1994). MHC class I and/or class II peptide complexes have been reported as being recognized by human T-cells. The ability to activate T-cells by cytokines or co-stimulatory molecules is thus extremely important.
The identification of human carcinoma associated antigens and epitopes that might be recognized by human T-cells is also currently under active investigation. Molecules such as prostate specific antigen (PSA), [Oesterling, J. E., J Urol 145: 907-923, (1991); Peace, D. J., et al Cancer Vaccine Symposium. Cancer Research Institute. Oct. 3-5 (1994)], neu/c-erbB2 [Fisk, B., et al. Int J Oncology 5: 51-63 (1994)] MUC-1 [Ioannides, C. G., et al. J Immunol 151: 3693-3703, (1993)] point mutated ras [Tsang, K. Y., et al. Vaccine Research (in press); Jung, S., et al. J Exp Med 173: 273-276 (1991); Fenton, S., et al. J Natl Cancer Inst 85: 1294-1302, (1993)] point mutated p53 [Houblers, J.G.A., et al Eur J Immunol 23: 2072-2077, (1993)] and carcinoembryonic antigen (CEA) [Kantor, J., et al. J Natl Cancer Inst 84: 1084-1091, (1992); Kantor, J., et al Cancer Res 52: 6917-6925, (1992); Ras, E., et al. European Immunology meeting, Barcelona, June (1994)] are among such candidates. One difficulty has been that many of these antigens are normal self-antigens, which therefore are not expected to trigger an immune response of the type needed for therapeutic approaches.
For example, while human CEA is extensively expressed on the vast majority of human colorectal, gastric and pancreatic carcinomas as well as approximately 50% of breast cancers and 70% of non-small cell lung cancers [Thompson, J. A., et al. J Clin Lab Anal 5: 344-366, (1991)], CEA is also expressed at least to some extent on normal colon epithelium and in some fetal tissue. The CEA gene has been sequenced and shown to be part of the human immunoglobulin gene superfamily, and thus shares some homology with other molecules found on normal human tissues. Thompson, J. A., et al. J Clin Lab Anal 5: 344-366, (1991); Oikawa, S., et al. Biochem Biophys Res Commun 144: 634-642, (1987). At the amino acid level, CEA shares approximately 70% homology with NCA (non-specific cross reacting antigen) which is found on normal granulocytes. Thompson, J. A., et al. supra.
However, the immunogenicity of CEA in normal humans or cancer patients is at best suspect. Although several papers claim antibodies to CEA in patients, [Staab, H. J., et al Br J Cancer 42: 26-33, (1980); Mavligit, G. M., et al. Cancer (Phila) 52: 146-149, (1983)] others claim these observations are artifacts [Collatz, E., et al Int J Cancer 8: 298-303, (1971); Chester, K. A., et al Clin Exp Immunol 58: 685-693, (1984); Ura, Y., et al. Cancer Lett 24: 283-295, (1985)]. No reports of the presence or absence of T-cell responses to CEA exist.
There are two types of immune response--antigen specific responses producing antibodies, and cell specific responses eliciting cytotoxic T-cells.
Improved methods for eliciting an immune response to self-antigen would be extremely useful.
For example, cytotoxic T-cells elicited by a self-antigen can be used in somatic cell therapy, in identifying epitopes and small peptides that induce a cytoxic T-cell response and in drug assays for compounds that enhance a specific cytoxic T-cell response.
The availability of human cytotoxic T-cells specific for carcinoma self-associated antigens also allow for mapping of the epitopes recognized by the T-cells. These epitopes can in turn be used to prime or boost the immune-system to expand the T-cell population either in vivo or in vitro. The in vitro cells as aforesaid can then be transferred back into a patient as is currently done in TIL cell therapy and used to treat a tumor expressing the antigen.